key: cord-1039357-yzorryn7 authors: Brufsky, Adam; Lotze, Michael T. title: Ratcheting down the virulence of SARS‐CoV‐2 in the COVID‐19 pandemic date: 2020-06-03 journal: J Med Virol DOI: 10.1002/jmv.26067 sha: 50c2bc624e86194d90bff93944a06f33b8ee7595 doc_id: 1039357 cord_uid: yzorryn7 Muller's Ratchet predicts that when mutation rates are high and a significant proportion of mutations are deleterious, a kind of irreversible ratchet mechanism will gradually decrease the mean fitness of small populations of asexual organisms. This article is protected by copyright. All rights reserved. To the Editor, Muller's ratchet 1 predicts that when mutation rates are high and a significant proportion of mutations are deleterious, a kind of irreversible ratchet mechanism will gradually decrease the mean fitness of small populations of asexual organisms. 2 Although RNA viruses typically have the ability to change rapidly (HIV and HCV) creating so-called quasi-species with profound differences in viral replicants due to the infidelity latent in the RNA polymerases, this appears to be less so with proofreading enzymes enabling restitution in the CoVs. Viral fitness is largely determined by the ability to propagate within the host and the host species, some reflecting that the most virulent strains are less successful from a broad host/pathogen perspective given that it ultimately limits viral spread. Genetic bottlenecks are created by interaction of viral variants and their host revealing a narrow range of genotypes successful over time. 6 Genetic bottlenecks are likely to occur quite frequently with RNA-based respiratory viruses since respiratory droplets often contain only one to two infectious particles per droplet. 7 Modeling suggests that such bottlenecks likely drive down the virulence of a pathogen due to stochastic loss of the most virulent phenotypes. 8 There may be evidence of bottleneck genetic selection with other viruses. In Ebola, mutations arose during the 2013 to 2016 outbreak which were postulated to increase or decrease virulence. 9 In a macaque model of Ebola, attenuation was suggested, as monkeys The relation of recombination to mutational advance Rapid fitness losses in mammalian RNA virus clones due to Muller's ratchet Genetic bottlenecks in intraspecies virus transmission The two faces of mutation: extinction and adaptation in RNA viruses Evaluation of a recombination-resistant coronavirus as a broadly applicable, rapidly implementable vaccine platform Genetic bottlenecks reduce population variation in an experimental RNA virus population Dynamics of infectious disease transmission by inhalable respiratory droplets Transmission bottlenecks as determinants of virulence in rapidly evolving pathogens Naturally occurring single mutations in ebola virus observably impact infectivity Recently identified mutations in the Ebola virus-Makona genome do not alter pathogenicity in animal models Attenuation of replication by a 29 nucleotide deletion in SARS-coronavirus acquired during the early stages of human-to-human transmission Evolution of the SARS coronavirus during the course of the SARS epidemic in China Distinct viral clades of SARS-CoV-2: implications for modeling of viral spread Analysis of the mutation dynamics of SARS-CoV-2 reveals the spread history and emergence of RBD mutant with lower ACE2 binding affinity Spike mutation pipeline reveals the emergence of a more transmissible form of SARS-CoV-2 DC/L SIGNs of hope in the COVID-19 pandemic Patient-derived mutations impact pathogenicity of SARS-CoV-2 A SARS-CoV-2 protein interaction map reveals targets for drug repurposing Discovery of a 382-nt deletion during the early evolution of SARS-CoV-2 An 81 nucleotide deletion in SARS-CoV-2 ORF7a identified from sentinel surveillance in Arizona